Download A Retrospective Study of Buprenorphine and

lournal of Analytical Toxicology, Vol, 23, October 1999
A RetrospectiveStudy of Buprenorphineand
Norbuprenorphine in Human Hair After Multiple Doses
Diana G. Wilkins 1,', Douglas E. Rollins 1, Angelique S. Valdez 1, Atsuhiro Mizuno 1, Gerald G. Krueger 2,
and Edward J. Cone 3
ZCenter for Human Toxicology,Departmentof Pharmacologyand Toxicology, Universityof Utah, 20 S 2030 East,Room490,
Salt LakeCity, Utah 84712;2Division of Dermatology,School of Medicine, Universityof Utah, Salt Lake City, Utah 84172;
and 3IntramuralResearchProgram,National Instituteon Drug Abuse, Baltimore,Maryland 21146
Abstract
Introduction
The analysisof hair has been proposed as a tool for monitoring
drug-treatment compliance. This study was performed to
determine if buprenorphine (BPR) and norbuprenorphine (NBPR)
could be detected in human hair after controlled administration
of drug and to determine if segmental analysis of hair was an
accurate record of the dosing history. Subjects with dark hair
(six males, six females) received 8 mg sublingual BPR for a
maximum of t 80 days. Single hair collections were made once
after BPR treatment and stored at -20~ until analysis. Hair was
aligned scalp-end to tip and then segmented in 3-cm sections.
For this study, it was assumedthat the mean hair growth rate
was 1.0 cm/month. Deuterated internal standard was added
to hair segments(2-20 mg of hair) and digested overnight at
room temperature with 1N NaOH. Specimenswere extracted
with a liquid-liquid procedure and analyzed by liquid
chromatography-tandem massspectrometry. The limits of
quantitatinn for BPR and NBPR were 3 pg/mg and 5 pg/mg,
respectively, for 20 mg of hair. BPR and NBPR concentrations
were highest for all subjects in hair segmentsestimated to
correspond to the subject's period of drug treatment. With one
exception, NBPR was present in higher concentrations in hair
than was the parent compound. BPR concentrations in hair
segments ranged from 3.1 pg/mg to 123.8 pg/mg. NBPR
concentrations ranged from 4.8 pg/mg to 1517.8 pg/mg.
In one subject, BPR and NBPR were not detected in any hair
segment. In some subjects, BPR and NBPRwere detected in
hair segmentsthat did not correspond to the period of drug
treatment, suggestingthat drug movement may have occurred
by diffusion in sweat and other mechanisms.The data from this
study also indicate that there is a high degree of intersubject
variability in measured concentration of BPR and NBPR in hair
segments, even when subjects receive the same dose for an
equivalent number of treatment days. Future prospective studies
involving controlled drug administration will be necessaryto
evaluate whether hair can serve as an accurate historical record
of variations in the pattern of drug use.
* Addresscorrespondenceto DianaG. Wilkins, Ph.D.,Centerfor HumanToxicology,20 South
2030 East,Room490, Universityof Utah, Saltlake City, Utah84112.
A potential use of hair analysis for drugs is the monitoring
of treatment compliance and recidivism. Hair may serve as a
historical record of drug exposures (1-3). It has been proposed
that knowing the rate of hair growth in an individual and the
location of the drug along the long axis of the hair shaft will
allow determination of the approximate time of drug use.
Treatment compliance would be indicated by the detection of
therapeutic drug in hair segments corresponding to periods of
therapeutic-drug treatment. Noncompliance in a drug-treatment program would be determined by gaps in the detection of
the therapeutic drug in hair segments predicted to contain
drug. Drug recidivism would be detected by finding an abused
drug in a hair segment that corresponds to a supposed abstinence period. Improved methods for determining patient compliance over time would be very useful to clinicians because
drug concentrations in plasma, urine, and saliva often reflect
only the dosage taken within the last several hours to days prior
to sampling. However,there are conflicting data regarding the
utility of hair analysis for drug monitoring (4-23).
In the United States, buprenorphine (BPR) is a drug currently under investigation for the treatment of heroin addiction
and is of interest for compliance-monitoring purposes. BPR is
a p opioid receptor partial agonist reported to produce minimal
withdrawal symptoms, low potential for overdose, long duration of action, and the ability to block heroin effects (24). BPR
has been demonstrated to be metabolized to buprenorphineglucuronide and partly to N-dealkylated product, norbupenorphine (NBPR) (25,26). Measurement of these drug
metabolites in hair may be useful to determine that an actual
ingestion, rather than external contamination of the hair from
the environment, has occurred (1). If hair analysis is to have
utility for compliance- or recidivism-monitoring purposes,
then certain fundamental principles of drug disposition in
hair, such as the predictable movement of a drug such as BPR
along the hair shaft, must be demonstrated.
Reproduction (photocopying) of editorial content of this journal is prohibited without publisher's permission.
409
Journal of Analytical Toxicology, Vol. 23, October 1999
This study was performed to determine if BPR and NBPR
could be detected in human hair after controlled administration of drug and to determine if segmental analysis of hair
was an accurate record of dosing history. Analysis of hair segments was performed to determine if the presence of drug in
individual segments correlated with the period of drug treatment.
Experimental
Chemicals and reagents for analytical methods
BPR, NBPR, and BPR-d4 reference materials were obtained
from Radian Corp. (Austin, TX). NBPR-d4was obtained from
Isotec Inc. (Miamisburg,OH). Separate lot numbers and weighings of reference materials from Radian or Isotec of BPR and
NBPRwere used for preparing quality-control samples for accuracy evaluation.
Methanol, n-butyl chloride, and acetonitrile (high-performance liquid chromatography [HPLC] grade) were obtained
from Burdick & Jackson Co. (Muskegon, MI); nitrogen was
obtained from Mountain Alrgas, Inc. (Salt Lake City, UT). All
other reagent-grade chemicals were obtained from Mallinckrodt Chemical Works (St. Louis, NO). All drug solutions were
prepared in HPLC-grade methanol or distilled water (MilliQ|
Milford, WI), as necessary. HPLC-gradesolvents were used in
extraction procedures.
Hair experiments
Collection of hair. l~velve healthy volunteers with a history
of drug use participated in an outpatient treatment study conducted at the Division of Intramural Research, NIDA.Medical
screening and psychological testing were performed to ensure
that subjects were healthy prior to participation in the study.
All subjects provided informed consent and were paid for their
participation. Six males and six females with dark hair received 8 mg sublingual BPR daily for up to 180 days. A single
lock of hair was collected from each subject (see Table I) and
stored at -20~ until analysis. Hair was collected based upon
subject availability. Therefore, some subjects had specimens
collected during the treatment interval and others after completion of treatment.
Segmentation of hair. Hair was aligned scalp-end to tip and
segmented in 3-cm sections. Itwas assumed that the mean hair
growth rate was 1.0 cm/month. Therefore,it was estimated that
a single 3-cm segment corresponded to an approximately
three-month time frame. The first seven segments (or 21 cm)
closest to the scalp were analyzed for BPR and NBPR.Hair segments beyond the first 21 cm of hair length were not analyzed
in this study.
Table I. Subject Demographic and Treatment Information
Numberof
Date of
Subject
Age
treatment Treatment
hair
ID
Ethnicity* Gender (years)
days
periodf
collection
A
C
F
27
180
B
C
M
35
180
C
C
F
26
180
D
C
M
25
180
7/5/8912/31/89
3/24/899/19/89
11/I/894/29/90
10/5/88-
Hair
length
(cm)
4/5/90
> 21.0
4/2/90
7.0
4/2/90
> 21.0
5/14/90
> 21.0
11/14/89- 4/3/90
5/12/90
1/20/89- 4/16/90
7118189
7 / 1 9 / 8 9 - 4/30/90
12/5/89
9/20/894/9/90
1/30/90
11/22/89- 5/14/90
2/4/90
5/30/895/7/90
8/4/89
5/28/895/7/90
7/6/89
11/1/894/6/90
12/I 0/89
7.4
4/2/89
E
C
M
32
180
F
C
F
38
180
G
C
M
39
135
H
A
F
32
133
I
C
F
26
74
J
C
M
31
67
K
C
M
35
42
L
C
F
32
40
* Abbreviations: C = Caucasian, A = African American.
f "Treatment period" refers to the period of time across which buprenorphine was administered.
410
13.3
10.9
> 21.0
> 21.0
12.2
11.4
> 21.0
Liquid chromatography-tandem mass
spectrometry of BPR and NBPR in hair
Hair specimens were analyzed using a
previously described liquid chromatographytandem mass spectrometry (LC-MS-MS) survivor ion procedure (27). Briefly, 5 ng/mg of
deuterated internal standard was added to 20
mg of hair. Specimens were solubilized (digested) overnight at room temperature in 2
mL of 1N NaOH. The following day, the pH
was adjusted to 10.5 and digests buffered with
1 mL of sodium bicarbonate buffer. Digests
were then extracted with n-butyl chloride/acetonitrile (4:1, v/v), evaporated to dryness, and
reconstituted in 75 IJL of water/acetonitrile
(2:1) prior to analysis. Extracts were analyzed
on a Finnigan TSQ~M7000with atmospheric
pressure ionization (27,28). Chromatographic
separation was achieved on an Alltech C8 Solvent Miser| column (2.1 x 150 ram) with an
isocratic mobile phase of H~O/MEOH/ACN
(25:30:45) containing 1% formic acid. The
MS was operated in MS-MS mode with a collision energy of-25 eV and 2.5 retort argon
collision gas pressure. Both Q1 and Q2 were
set to monitor ions at rn/z 468 (BPR) and 414
(NBPR) (27).
Standards and quality-control specimens
were concurrently extractedwith all assays and
prepared by fortifying drug-free human hair
with known amounts of BPR and NBPR. Be-
Journal of Analytical Toxicology, Vol. 23, October 1999
cause it is unknown whether fortified hair standards and
quality controls adequately evaluate the effectivenessof the digestion process (i.e., release of incorporated drug from hair
shaft structures), additional samples were included in some assays. These samples consisted of hair from rats who had received intraperitoneal BPR once per day for five days and were
used to verify reproducibility of the assay. Quantitative data for
these specimens have been previously published (29). Also,
quality-control specimens consisting of human hair fortified
with BPR (only) were prepared to assess whether BPR was
converted to NBPRduring digestion, extraction, and analytical
procedures. Data from these quality-control specimens indicated that no conversion (degradation) of BPR to NBPR occurred during these procedures.
The limits of quantitation for BPR and NBPRby LC-MS-MS
were 3 pg/mg and 5 pg/mg, respectively, for 20 mg of hair. The
assay was linear for both BPR and NBPR to 50 ng/mg. Intraassay precision was 12% at 10 pg/mg (BPR) and less than 10%
at 100 pg/mg, 1 ng/mg, and 25 ng/mg (BPR and NBPR).
Results
Table I presents the available information for subjects with
respect to demographic and treatment information. Males
(n = 6) and females (n = 6) ranging in age from 26 to 39 years
participated in the study. One African-Americansubject and 11
Caucasian subjects were enrolled, and all subjects had dark
brown to black hair. Six subjects received 8 mg sublingual
BPR for the maximum of 180 days, and six subjects received
BPR for less than 180 days. A single lock of hair was collected
at least six months after initiation of BPR treatment as indicated in Table I. The column labeled "Treatment period" refers
to the period of time across which sublingual BPR was administered. Comparison of the dates of treatment and the date
of hair collection demonstrates that at the time of hair collection, some subjects had not received BPR for several months
and other subjects were still actively receiving BPR. Detailed
data regarding hygiene and chemical treatments for each subject were not available at the time of collection.
Figures 1A-1Lpresent the segmentation data obtained from
each of 12 subjects participating in the study. Three-centimeter
segments of hair were analyzed, and quantitative data for BPR
and NBPR were obtained for each segment. Bar graphs were
constructed so that hair segment 1, closest to the scalp at the
time of collection, is closest to the origin. Based on the dates between which treatment occurred (see Table I), the predicted tocation of drug is indicated immediately below the bar graph. In
5 of the 12 subjects (A, B, C, H, and J), the first 3 cm of hair
closest to the scalp was not available for analysis. This first segment had been previously consumed in other drug analyses
and insufficienthair remained for the analysis of BPR. These unavailable hair segments are indicated in Figures 1A-1Las "NA."
The data represented in the bar graphs in Figure I demonstrate that both BPR and its metabolite NBPRwere detected in
11 of 12 subjects who were known to have received BPR
therapy. In these subjects, BPR and NBPR concentrations were
greatest in hair segments corresponding to the period of active
drug treatment. However, in 9 of 12 subjects (A, B, C, D, E, G,
H, I, and K), parent drug or metabolite was also detected in
hair segments that did not correspond to the period of drug
treatment.
After multiple 8-rag sublingual doses of BPR, hair concentrations of BPR ranged from 3.1 pg/mg to 123.8 pg/mg. NBPR
concentrations ranged from 4.8 pg/mg to 1517.8 pg/mg. With
one exception (B), NBPR was always present in higher concentrations in individual hair segments than was the parent
compound. One subject (F) did not have BPR or NBPR in any
hair segment, despite the known dosing history. A high degree
of intersubject variability in measured concentration of BPR
and NBPRwas observed, even when subjects received the same
8-rag dose for an equivalent number of treatment days.
Discussion
BPR or NBPRwas detected in 11 of 12 subjects who had received controlled 8-rag doses of sublingual BPR in a treatment setting. The order of magnitude of our quantitative
results (picograms-per-milligram range) for these 11 subjects
is consistent with those previously reported by other investigators (30,31). The highest concentrations of BPR and NBPR
were detected in hair segments estimated to correspond to
the period of active drug treatment (see solid bars under bar
graphs in Figure 1). In contrast to earlier reports, however, we
found that the NBPR metabolite was detected in hair in higher
concentrations than was the parent BPR compound. When
both BPR and NBPR were present in hair segments corresponding to periods of active drug treatment, a ratio of at least
1:3 was observed. Only 1 of these 11 subjects (B) did not
demonstrate this ratio for the period of active drug treatment.
It has been suggested that at least one of the major routes of
drug incorporation into hair is via distribution from plasma
into growing hair cells (1,2). Recent data from Kuhlman et al.
(32) demonstrated that NBPR accumulates in plasma after
chronic administration of BPR and that the plasma concentrations exceed those of the parent BPR compound. The mean
steady-state BPR plasma concentration after daily administration of sublingual BPR for 21-35 days was 0.8 ng/mL. The
mean steady-state NBPR plasma concentration was 1.10
ng/mL. These findings may help explain the ratio of parent
drug and metabolite obtained in hair specimens from our
study.
The inconsistency between the data in our study and those
of previous investigators may be explained by the difference in
sublingual BPR doses received by subjects. The subjects in
our study may have received substantially higher daily sublingual doses of BPR than the subjects in the earlier reports.
There may also have been a difference in the number of days of
drug treatment prior to collection of hair specimens. Because
the previous reports did not include specific information for
each subject with respect to doses received or time of hair
collection, we are unable to evaluate these differences further.
Additional studies on the pharmacokinetics of BPR and its
411
Journal of Analytical Toxicology, Vol. 23, October 1999
metabolites with respect to hair and plasma are necessary to
elucidate the pattern and quantitative distribution of BPR and
NBPR into hair.
Another possible explanation for our finding of higher NBPR
concentrations is related to the stability of specimens upon
prolonged storage. Our data demonstrate that BPR and NBPR
can be readily detected in individual hair segments despite
Subject
prolonged periods of storage. However, the locks of hair in
this study were stored at -20~ for up to seven years prior to
analysis, and there are no published studies on the effect of
storage conditions on the stability of BPR and its metabolites
in hair. It is unclear to what extent this may have affected our
quantitative results. Our laboratory is currently conducting a
prospective study of sublingual BPR administration, with spec-
A
Subject
440.5
D
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(Apr 90Jen 90)
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(J~
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(July 09.
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Figure 1. Bar graphs of buprenorphine and norbuprenorphine concentrations in individual hair segments after multiple doses. Lightly hatched bars indicate measured hair concentrations of buprenorphine. Densely hatched bars indicate measured hair concentrations of norbuprenorphine. The intersection
of the x and y axes indicate the date of hair collection; therefore, the end of the hair closest to the scalp is closest to the origin. The predicted location of
drug in the available hair specimen is indicated immediately below the bar graph.
412
Journal of Analytical Toxicology, Vol. 23, October 1999
imens analyzed for BPR and NBPRafter a few weeks of storage.
Although that study is still in progress, data for the first four
subjects indicate that the distribution and quantitative values
of BPR and NBPR are consistent with those observed in this
retrospective study (33); NBPR hair concentrations are consistently greater than those of the parent compound. These
data indicate that degradation of BPR to NBPR due to pro-
longed storage is an unlikely explanation for our findings.
Hair specimens in this study were not washed immediately
prior to analysis. Subjects did, however, perform normal hygienic practices such as hair washing over the weeks and
months encompassed by this study. It is possible that the lack
of a laboratory-based hair-washing procedure may have contributed to our finding of higher NBPR concentrations than
G
Subject
Subject
SO
J
~4,e
,500
m
40
400
e. 3 ;
30
.|
.
u
20010-
>
N~.
0
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.''--.
(,.J .o- (~.,~,
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location
J~ ~o)
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100
(~?..
o:1 a~)
II
4
I
1
0
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~u~ e0}
.~ Tip
P~KIIcteU
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g2.8
I i
,
(Mly1
e~ 8O)
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Se$ment
(Aug BgMay 89)
Aug 69)
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800-
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=
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m
o
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20
~78.0
16.7
e.s
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Jan go)
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location
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IocMkm
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Subject
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Nov . )
u
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location
Scalp
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Figure 1. (continued) Bar graphs of buprenorphine and norbuprenorphine concentrations in individual hair segmentsafter multiple doses. Lightly hatched
bars indicate measured hair concentrations of buprenorphine. Densely hatched bars indicate measured hair concentrations of norbuprenorphine. The intersection of the x and y axes indicate the date of hair collection; therefore, the end of the hair closest to the scalp is closest to the origin. The predicted
location of drug in the available hair specimen is indicated immediately below the bar graph.
413
Journal of Analytical Toxicology,Vol. 23, October 1999
BPR in hair, assuming that there is a differential effect of removal between BPR and NBPR. Because of this possibility, a
very brief evaluation was conducted on the effect of two different wash procedures on quantitative results of NBPR in
human and rat hair. Wash condition A consisted of 2 mL of
methanol; wash condition B consisted of 2 mL dry isopropanol,
followed by 2 mL of phosphate buffer (pH 5.6). Hair specimens were washed under one of each of these conditions until
no more BPR or NBPR could be detected in the wash solution.
Depending on the wash condition, BPR and NBPR concentrations in human hair decreased from 12.9% to 100.0%. Rat
hair specimens showed a similar pattern of decrease. NBPR
concentrations in human hair remained higher than those of
BPR. Therefore, although the inclusion of a wash procedure
may have decreased the overall quantitative results, it is unlikely to be an explanation for the high NBPR concentrations.
Nine of 12 subjects (A, B, C, D, E, G, H, I, and K) had BPR or
NBPR in hair segments that did not correspond to the period
of drug treatment. There are two probable interrelated explanations for these findings. First, a major assumption was made
in estimating the hair growth rate at 1.0 cm/month for the
preparation of these bar graphs. According to available literature, hair growth rates for scalp hair can actually vary between
0.6 and 3.36 cm/month (34,35). Because of this variability, it is
possible that the hair segments immediately before (indicating
more slowly growing hairs) and immediately after (indicating
more rapidly growing hairs) those predicted for the period of
drug treatment may contain some drug or metabolite. We
then re-examined our data, excluding these hair segments, to
determine which subjects would continue to have segmentation results that were inconsistent with the dosing history. In
this case, five subjects (A, C, D, H, and I) still had BPR or
NBPR detected in hair segments that did not correspond to the
periods of active drug treatment. These data suggest that a
second explanation is also involved.Drug movement may occur
in hair via diffusion in sweat and by other mechanisms, such as
movement of compounds within the hair shaft as a result of
normal hygienic practices. Regardless of the mechanism involved, the detection of parent compound or metabolite in
hair segments that do not correspond to the period of drug
treatment is of concern.
Finally, a high degree of intersubject variability in measured
concentrations of BPR and NBPR was observed in 3-cm hair
segments, even when subjects received the same 8-rag dose for
an equivalent number of treatment days. We cannot totally
eliminate the possibility that BPR was ingested by some subjects from sources outside the residential unit, particularly
after discharge from treatment. However, there were no "takehome" medication privileges during the study, and the availability of outside sources of BPR was highly unlikely in the
United States at the time of the study. The large variability in
measured hair concentrations might also be due to the differences in the length of time between which BPR administration
was discontinued and hair specimens were collected (see Table
I). Also, there may have been subtle differences in the collection process with respect to the distance from the scalp (millimeters) at which hair was cut. In addition, animal studies
have suggested that the deposition of BPR into hair is greater
414
in pigmented than nonpigmented hair (29). It is possible that
the variable melanin content in dark-colored human hair from
subjects in our study may have influenced the deposition of
buprenorphine into hair.
As suggested by many authors, other biological, physiological, and environmental factors may also play a role in affecting
the amount of drug incorporated into hair (1,2,36,37). Other
probable sources of variability include differences in hair structural characteristics, drug metabolism, contribution from
sweat, or other routes of drug incorporation into hair. The
high degree of variability in BPR and NBPR concentrations in
hair segments will make it difficult to interpret time- and concentration-relationships in human hair.
Conclusions
The data from this retrospective study demonstrate that
BPR and NBPR can be detected in human hair segments after
an 8-mg sublingual dose with metabolite concentrations
greater than those of parent compound. The highest concentrations of BPR and NBPR were detected in hair segments estimated to correspond with a period of active drug treatment.
However, BPR and NBPR were also detected in hair segments
that did not correspond to periods of drug treatment, suggesting that drug movement may occur in hair via diffusion in
sweat and by other mechanisms. The limitations of this retrospective study preclude a definitive explanation for these observations. Future prospective studies involving controlled
drug administration will be necessary to evaluate whether hair
can serve as an accurate historical record of variations in the
pattern of drug use. Such studies will be also be needed to determine if hair analysis can be useful for monitoring treatment compliance.
Acknowledgments
The authors wish to thank Dr. John Laycock and Mr. Alan
Spanbauer for their valuable assistance in the analysis of
buprenorphine specimens. This research was supported by
NIDA Grant No. DA09096.
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Manuscript received March 4, 1999;
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415